Substituted furo[2,3-g]indazoles for the treatment of glaucoma

ABSTRACT

Substituted furo[2,3-g]indazoles for lowering intraocular pressure and treating glaucoma are disclosed.

This application claims priority from U.S. Provisional Application, Ser.No. 60/525,635 filed Nov. 26, 2003.

BACKGROUND OF THE INVENTION

The present invention relates to the use of substituted furanoindazolesfor lowering and controlling normal or elevated intraocular pressure(IOP) and for treating glaucoma.

The disease state referred to as glaucoma is characterized by apermanent loss of visual function due to irreversible damage to theoptic nerve. The several morphologically or functionally distinct typesof glaucoma are typically characterized by elevated IOP, which isconsidered to be causally related to the pathological course of thedisease. Ocular hypertension is a condition wherein intraocular pressureis elevated but no apparent loss of visual function has occurred; suchpatients are considered to be at high risk for the eventual developmentof the visual loss associated with glaucoma. If glaucoma or ocularhypertension is detected early and treated promptly with medicationsthat effectively reduce elevated intraocular pressure, loss of visualfunction or its progressive deterioration can generally be ameliorated.Drug therapies that have proven to be effective for the reduction ofintraocular pressure include both agents that decrease aqueous humorproduction and agents that increase the outflow facility. Such therapiesare in general administered by one of two possible routes, topically(direct application to the eye) or orally.

There are some individuals who do not respond well when treated withcertain existing glaucoma therapies. There is, therefore, a need forother topical therapeutic agents that control IOP.

Serotonergic 5-HT_(1A) agonists have been reported as beingneuroprotective in animal models and many of these agents have beenevaluated for the treatment of acute stroke among other indications.This class of compounds has been mentioned for the treatment of glaucoma(lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.)and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol.210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT)(a 5-HT_(1A) agonist) reduces IOP in rabbits. Wang, et al. (Current EyeResearch, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488,March, 1998) indicate that 5-methylurapidil, an α_(1A) antagonist and5-HT_(1A) agonist lowers IOP in the monkey, but attribute the IOP effectto its α_(1A) receptor activity. Also, 5-HT_(1A) antagonists aredisclosed as being useful for the treatment of glaucoma (elevated IOP)(e.g., WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) andMacor, et al. (U.S. Pat. No. 5,578,612) relate to the use of 5-HT₁ and5-HT_(1-like) agonists for the treatment of glaucoma (elevated IOP).These anti-migraine compounds, e.g., sumatriptan and naratriptan andrelated compounds, are 5-HT_(1B,D,E,F) agonists.

It has been found that serotonergic compounds which possess agonistactivity at 5-HT₂ receptors effectively lower and control normal andelevated IOP and are useful for treating glaucoma, see commonly ownedco-pending application, U.S. patent application Ser. No. 09/787,332corresponding to WO 00/16761, both of which are incorporated in theirentirety by reference herein. Compounds that act as agonists at 5-HT₂receptors are well known and have shown a variety of utilities,primarily for disorders or conditions associated with the centralnervous system (CNS). U.S. Pat. No. 5,494,928 relates to certain2-(indol-1-yl)-ethylamine derivatives that are 5-HT_(2C) agonists forthe treatment of obsessive compulsive disorder and other CNS derivedpersonality disorders. U.S. Pat. No. 5,571,833 relates to tryptaminederivatives that are 5-HT₂ agonists for the treatment of portalhypertension and migraine. U.S. Pat. No. 5,874,477 relates to a methodfor treating malaria using 5-HT_(2A/2C) agonists. U.S. Pat. No.5,902,815 relates to the use of 5-HT_(2A) agonists to prevent adverseeffects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT_(2B)agonists for the treatment of depression and other CNS conditions. WO00/12475 relates to indoline derivatives, and WO 00/12510 and WO00/44753 relate to certain indole derivatives as 5-HT_(2B) and 5-HT_(2C)receptor agonists for the treatment of a variety of disorders of thecentral nervous system, but especially for the treatment of obesity. WO00/35922 relates to certain pyrazino[1,2-a]quinoxaline derivates as5-HT_(2C) agonists for the treatment of obsessive compulsive disorder,depression, eating disorders, and other disorders involving the CNS. WO00/77002 and WO 00/77010 relate to certain substituted tetracyclicpyrido[4,3-b]indoles as 5-HT_(2C) agonists with utility for thetreatment of central nervous system disorders including obesity,anxiety, depression, sleep disorders, cephalic pain, and social phobiasamong others. WO 02/40456 and WO 03/00663 relate to certain substituted1-(pyrazinyl)-piperazines and substituted 1-(pyrimidinyl)-piperazines,respectively, as agonists or antagonists at 5-HT_(2C) receptors for thetreatment of a variety of central nervous system related disorders,especially obesity and sexual dysfunction. Agonist response at the5-HT_(2A) receptor is reported to be the primary activity responsiblefor hallucinogenic activity, with some lesser involvement of the5-HT_(2C) receptor possible [Psychopharmacology, Vol. 121:357, 1995].

Few furan or pyran containing fused indazoles have been reported. Thechemical synthesis of 7-methyl- and 1,7-dimethyl-1H-furo[2,3-g]indazole[Gazz. Chim Ital. 106, 1083 (1976)] as well as that of 3-methyl- and1-(4-aminophenyl)-3-methyl-1H-benzo[b]furo[2,3-g]indazole [An. Asoc.Quim. Argent. 59, 69 (1971)] has been reported without discussion oftheir utility. European Patent Application EP 990,650 (Intnl.Publication Number WO 98/56768) relates to substituted2-(furo[2,3-g]indazol-1-yl)-ethylamines, such as(S)-2-(furo[2,3-g]indazol-1-yl)-1-methylethylamine, which are reportedto have high selectivity and affinity for 5-HT_(2C) receptors and arepotentially useful for treating a variety of central nervous systemdisorders. The chemical synthesis of9-methyl-1H-pyrano[2,3-g]indazol-7-one and the correspondingnon-methylated compound was reported [Indian J. Chem. 26B, 436 (1987)]with no mention of utility.

U.S. Pat. Nos. 5,561,150 and 5,646,173 relate to certain tricyclicpyrazole derivative compounds which are identified as being 5-HT_(2C)agonists for the treatment of CNS diseases and are primarily directed tolipophilic analogs that have a high probability of entering the brain.Similarly, WO 98/56768 relates to tricyclic 5-HT_(2C) agonists for thetreatment of CNS diseases. All the patents and publications mentionedabove and throughout are incorporated in their entirety by referenceherein.

5-Hyroxytyptamine (serotonin) does not cross the blood-brain barrier andenter the brain. However, in order to increase brain serotonin levelsthe administration of 5-hydroxy-tryptophan can be employed. Thetransport of 5-hydroxy-tryptophan into the brain readily occurs, andonce in the brain 5-hydroxy-tryptophan is rapidly decarboxylated toprovide serotonin.

Accordingly, there is a need to provide new compounds which avoid thedisadvantages described above and which provide increased chemicalstability and a desired length of therapeutic activity, for instance, indecreasing intraocular pressure and treating glaucoma.

SUMMARY OF THE PRESENT INVENTION

A feature of the present invention is to provide novel compounds whichare 5-HT₂ agonists.

Another feature of the present invention is to provide compounds whichhave increased chemical stability and which are useful in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

Another feature of the present invention is to provide compounds whichprovide a desired level of therapeutic activity in lowering andcontrolling normal or elevated intraocular pressure and/or treatingglaucoma.

Additional features and advantages of the present invention will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of thepresent invention. The objectives and other advantages of the presentinvention will be realized and attained by means of the elements andcombinations particularly pointed out in the description and appendedclaims.

To achieve these and other advantages, and in accordance with thepurposes of the present invention, as embodied and broadly describedherein, the present invention relates to a compound having the FormulaA:

and described more fully below.

The present invention further relates to pharmaceutical compositionscontaining at least one compound of Formula A.

The present invention further relates to methods to lower and/or controlnormal or elevated intraocular pressure by administering an effectiveamount of a composition containing a compound having Formula A asdescribed above.

The present invention also relates to a method for treating glaucomawhich involves administering an effective amount of a compositioncontaining a compound having Formula I as described above.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are intended to provide a further explanation of the presentinvention, as claimed.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a variety of compounds which are usefulaccording to the present invention. These compounds are represented bythe following Formula A.

-   Wherein R, R¹ and R² are independently chosen from hydrogen,    C₁₋₄alkyl;-   R³ is selected from hydrogen, C₁₋₄alkyl, or R² and R³ can complete a    pyrrolidine or piperidine ring, which can be substituted with    C₁₋₄alkyl;-   R⁴ is hydrogen, halogen, C₁₋₄alkyl;-   R⁵ and R⁶ are independently chosen from hydrogen, halogen,    C₁₋₆alkyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylsulfoxide,    nitrile, C₁₋₆alkyl substituted with halogen;-   R⁷ is chosen from C═OR⁹; S(O)_(m)R¹⁰; NR¹—(C═O)—R¹¹; C₁₋₆alkyl    substituted with hydroxyl, C₁₋₆alkoxy, OC(═O)C₁₋₈, CO₂H,    CO₂C₁₋₆alkyl, C(═O)NR¹²R¹³, S(O)_(m)NR¹²R¹³, NR¹⁴R¹⁵, phenyl or a    saturated or unsaturated 5 or 6-membered heterocyclic ring which can    contain 1-4 heteroatoms selected from N, O, or S and can be    unsubstituted or substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen,    haloC₁₋₄alkyl, phenyl or pyridinyl; or R⁷ can be chosen from a    heterocyclic ring selected from an oxazole such as oxazol-2-yl,    4,5-dihydro-oxazol-2-yl, or benzoxazol-2-yl, an oxazine such as    5,6-dihydro-[1,3]oxazin-2-yl, a thiazole such as thiazol-2-yl,    4,5-dihydro-thiazol-2-yl, or benzothiazol-2-yl, an imidazole such as    imidazol-2-yl, or imidazolidin-2-yl, [1,2,4]oxadiazol-5-yl,    [1,2,4]oxadiazol-3-yl, [1,2,4]thiadiazol-5-yl, or    [1,2,4]thiadiazol-3-yl which can be unsubstituted or substituted    with C₁₋₆alkyl, C₁₋₆alkoxy, phenyl or pyridinyl, or C₁₋₆alkyl    substituted with phenyl or pyridinyl;-   but R⁷ cannot be hydrogen, lower alkyl, hydroxyl, lower alkoxy,    amino, mono- or di-loweralkyl amino, lower alkanoylamino, or    halogen;-   R⁸ is selected from C₁₋₆alkyl, phenyl which can be substituted with    C₁₋₆alkyl, C₁₋₆alkoxy, NR¹(C═O)C₁₋₆alkyl, or halogen;-   R⁹ is chosen from hydroxyl; C₁₋₆alkoxy; C₁₋₆alkoxy substituted with    phenyl or pyridinyl which can be substituted with C₁₋₄alkoxy or    halogen; NR¹⁶R¹⁷; C₁₋₆alkyl; or C₁₋₆alkyl substituted with hydroxyl,    C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, S(O)_(m)NR¹²R¹³, halogen,    or phenyl or a heterocyclic ring selected from pyrrolidinyl,    imidazoyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl, or    tetrazolyl, or pyridinyl which can be unsubstituted or substituted    with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl;-   R¹⁰ is chosen from NR¹²R¹³; C₁₋₆alkyl; CH₂phenyl or CH₂pyridinyl    which can be substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, or    haloC₁₋₄alkyl; or C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy,    NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, phenyl, pyridinyl or imidazolyl which    can be substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen,    haloC₁₋₄alkyl;-   R¹¹ is NH₂; NR¹R²; C₁₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy,    CO₂H, CO₂C₁₋₆alkyl, phenyl or a saturated or unsaturated 5 or    6-membered heterocyclic ring which can contain 1-4 heteroatoms    selected from N, O, or S and can be unsubstituted or substituted    with C₁₋₆₋alkyl, C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl;-   R¹² and R¹³ are independently selected from hydrogen; C₁₋₆alkyl;    CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl,    thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can be    substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl;    C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, CO₂H, CO₂C₁₋₆alkyl,    NR¹COC₁₋₆alkyl, or halogen; or R¹², R¹³, and the intervening    nitrogen atom can form a heterocyclic ring selected from morpholine,    thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,    azetidine, pyrrolidine, piperidine, piperazine, unsubstituted or    substituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy,    C₁₋₄alkoxy or halogen;-   R¹⁴ and R¹⁵ are independently selected from hydrogen, C₁₋₆alkyl,    hydroxyl, C₁₋₆alkoxy, (C═O)—R¹¹, S(O)_(m)R⁸, phenyl or pyridinyl    which can be substituted with C₁₋₆alkyl, C₁₋₆₋alkoxy, halogen, or    haloC₁₋₄alkyl; or R¹⁴, R¹⁵ and the nitrogen atom to which they are    attached can form a heterocyclic ring selected from pyrrolidine,    piperazine, or piperidine, which can be substituted with C₁₋₆alkyl,    phenyl, or pyridinyl;-   R¹⁶ and R¹⁷ are independently selected from hydrogen; C₁₋₆alkyl;    hydroxyl; C₁₋₆alkoxy; CH₂Z, where Z is selected from phenyl,    pyridinyl, furanyl, thiophenyl, pyrimidinyl, pyrazinyl, or    pyridazinyl, and which can be substituted with C₁₋₆alkyl,    C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl; C₂₋₆alkyl substituted with    hydroxyl, C₁₋₆alkoxy, halogen, NR¹(C═O)C₁₋₆alkyl, or a phenyl or a    heterocyclic ring selected from a pyrrole, such as pyrrolidin-2-yl,    an imidazole such as imidazo-2-yl or imidazo-4-yl, a morpholine such    as morpholin-3-yl, a piperidine such as piperidin-4-yl, oxazolyl,    isoxazolyl, thiazolyl, tetrazolyl, pyridinyl, which can be    unsubstituted or substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen,    haloC₁₋₄alkyl, phenylC₁₋₄alkyl, oxo (═O); or R¹⁶, R¹⁷, and the    intervening nitrogen atom can form a heterocyclic ring selected from    morpholine, thiomorpholine, thiomorpholine 1-oxide, thiomorpholine    1,1-dioxide, azetidine, pyrrolidine, piperidine, piperazine,    unsubstituted or substituted with C₁₋₄alkyl or C₁₋₄alkyl substituted    with hydroxy, oxo (═O), C₁₋₄alkoxy, or phenyl;-   m is 0-2;-   A is N or CH; and-   X and Y are either N or C, wherein X and Y cannot be the same; and    the dashed bonds denote a suitably appointed single and double bond.

In the above definitions, the total number of carbon atoms in asubstituent group is indicated by the C_(i-j) prefix where the numbers iand j define the number of carbon atoms. This definition includesstraight chain, branched chain, and cyclic allyl or (cyclic alkyl)alkylgroups. A substituent may be present either singly or multiply whenincorporated into the indicated structural unit. For example, thesubstituent halogen, which means fluorine, chlorine, bromine, or iodine,would indicate that the unit to which it is attached may be substitutedwith one or more halogen atoms, which may be the same or different.

Synthesis

Compounds of Formula A can be prepared by using one of several syntheticprocedures. For example, esters of1-(2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid can beprepared from an appropriately protected1-(2-aminopropyl)-1H-furo[2,3-g]indazol-6-ol (1) either via thedihydrofuran intermediate 4 [Helv. Chim. Acta, 84:2198 (2001)] or by wayof the 7-formyl intermediate 3 as outlined in Scheme 1. As used herein,Pg denotes a suitable protective group to assure that a particular atomis not modified during the indicated chemical reaction. See, forexample, the use of carbobenzyloxy in the Examples below.

As described below, other compounds of Formula A can be prepared fromthe appropriately N-protected ester intermediates 5 through selectfunctional group transformations well-known in the art. For example,reaction of certain esters 5 with the desired primary or secondary amineor ammonia followed by deprotection will provide the desired7-carboxamide compounds 7 of Formula A. Alternatively, it may bepreferable to initially hydrolyze an ester 5 to the correspondingcarboxylic acid 8, which can be suitably activated, to such as with anappropriated carbodiimide reagent, and then reacted with the desiredamine to give, after deprotection, the desired 7-carboxamides. Yet othercompounds of Formula A can be prepared by initially reducing theintermediate ester or acid to the corresponding 7-hydroxymethylintermediate 9, which can subsequently be activated, such as byformation of an appropriate sulfonate ester, followed by reaction with adesirable nucleophile and suitable deprotection as outlined in Scheme 2.

Using the procedures described in Schemes 1-4 (above), the Examples 1-20(below), and well known procedures, one skilled in the art can preparethe compounds disclosed herein.

The following examples are given to illustrate the preparation ofcompounds that are the subject of this invention but should not beconstrued as implying any limitations to the claims. The preparation ofpreferred compounds of Formula A is described in Examples 3, 4, 10 and11, with Examples 4 and 11 describing the preparation of the mostpreferred compounds. The proton magnetic resonance spectrum of eachcompound of the Examples was consistent with the assigned structure.

EXAMPLE 1 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidethyl ester fumarate Step A:[(S)-2-(6-Hydroxy-indazol-1-yl)-1-methylethyl]-carbamic acid benzylester

1-((S)-2-Aminopropyl)-1H-indazol-6-ol [prepared in accordance withcommonly owned WO 02/098862A1, the contents of which are by thisreference incorporated herein] (2.00 g, 10.5 mmol) was suspended in THF(20 mL) and saturated aqueous sodium bicarbonate (10 mL) and benzylchloroformate (1.50 mL, 15 mol) were added. The mixture was stirred atroom temperature until the starting amine dissolved. Saturated aqueoussodium bicarbonate (150 mL) was added and the reaction mixture extractedwith ethyl acetate (3×150 mL). The combined organic layers were dried(magnesium sulfate), filtered, and evaporated to give a tan foam (2.65g, 78%) which was pure by LC/MS (+APCI) m/z 326 (M+H⁺).

Step B:[(S)-2-(6-Hydroxy-7-hydroxymethyl-indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

To a stirred solution of the product from Step A (2.2 g, 6.8 mol) in THF(30 mL) was added potassium hydroxide (3.3%, 5 mL) and aqeousformaldehyde (37%, 1.6 mL); this solution was heated at 55° C. for 2 hfollowed by stirring for an additional 18 h at room temperature. Asaturated ammonium chloride solution (30 mL) was added to the reactionmixture, which was extracted with ethyl acetate (3×50 mL). The combinedextracts were washed with brine (30 mL), dried and evaporated. Theresidue was purified by chromatography (silica, 50% ethyl acetate inhexane) to give 6 as an oil (2.2 g, 91%): ¹H NMR δ (DMSO-d₆) δ 7.87 (s,1H), 7.46 (d, 1H, J=8.5 Hz), 7.32 (m, 5H), 6.78 (d, 1H, J=8.5 Hz), 6.50(d, 1H, J=7.8 Hz), 4.78 (s, 2H), 4.68-4.48 (m), 1.03 (d, 3H, J=6.0 Hz);MS (ES) m/z 356 (M⁺).

Step C: [(S)-2-(7-Formyl-6-hydroxy-indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

To a stirred solution of the product from Step B (0.75 g, 2.11 mmol) intetrahydrofuran (10 mL) was added activated manganese dioxide (0.75 g)and the resultant solution was stirred for 18 h at 45° C. The solutionwas filtered through a filter aide and the filtrate was evaporated. Theresidue was purified by chromatography (silica, 30% ethyl acetate inhexane) to yield a solid (0.54, 72%): mp 135-137° C.; MS (ES) m/z 254(M⁺); ¹H NMR (CDCl₃) δ 13.18 (s, 1H), 10.77 (s, 1H), 7.90 (s, 1H), 7.57(d, 1H, J=8.0 Hz), 7.33-7.27 (m, 5H), 6.81 (d, 1H, J=8.0 Hz), 5.05 (m,3H), 4.70 (m, 1H), 4.52-4.47 (m, 1H), 4.23-4.19 (m, 1H), 1.22 (d, 3H,J=8.0 Hz).

Step D:1-((S)-2-Benzyloxycarbonylaminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid ethyl ester

To a stirred solution of the product from Step C (0.20 g, 0.56 mmol) inDMF (10 mL) was added potassium carbonate (0.23 g, 1.68 mmol) followedby ethyl 2-bromoacetate (0.07 mL, 0.62 mmol) at room temperature and theresultant solution was heated at 70° C. for 20 h. Saturated aqueousammonium chloride (20 mL) was added followed by ethyl acetate (50 mL).The organic layer was separated and the aqueous was extracted with ethylacetate (3×50 mL). The combined organic layers were washed with brine(30 mL), dried and evaporated. The residue was purified bychromatography (silica, 50% ethyl acetate in hexane) to give an oil(0.10 g, 42%): MS(ES) m/z 422 (M⁺); ¹H NMR (CDCl₃) δ 8.17 (s, 1H), 8.05(s, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.43 (d, 1H, J=8.8 Hz), 7.33 (m, 5H),5.05-5.09 (m, 2H), 4.58 (m, 1H), 4.30 (m, 2H), 1.45 (t, 3H, J=7.2 Hz),1.17 (d, 3H, J=6.8 Hz).

Step E: 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidethyl ester fumarate

To a solution of the product from Step D (0.10 g, 0.24 mmol) in ethanol(5 mL) under nitrogen was added Pd/C (10%, 0.01 g) and the suspensionwas stirred under a hydrogen atmosphere at room temperature for 18 h.The solution was filtered through a filter aide and the filtrate wasconcentrated to a residue, which was purified by chromatography (silica,dichloromethane, 10% methanol in dichloromethane and 15% methanol indichloromethane) to give a syrup (0.06 g, 88%). The syrup was dissolvedin methanol and combined with a solution of fumaric acid (0.02 g) inmethanol (1.0 mL). Evaporation of this mixture provided a residue thatsolidified from a mixture of methanol and ethyl acetate (0.06 g): mp184-185° C.; MS (ES) m/z 288 (M⁺); ¹H NMR (DMSO-d₆) δ 8.46 (s, 1H), 8.28(s, 1H), 7.93 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=8.8 Hz,), 6.55 (s, 3H),4.84-4.89 (m, 2H), 4.42 (q, 2H, J=7.2 Hz), 3.72 (m, 1H), 1.37 (t, 7H,J=7.2 Hz), 1.14 (d, 3H, J=6.4 Hz); Analysis. Calculated forC₁₅H₁₇N₃O₃.1.5 C₄H₄O₄.1.1 H₂O: C, 52.41; H, 5.28; N, 8.73. Found: C,52.18; H, 5.27; N, 9.12.

EXAMPLE 2 [1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-yl]-methanolStep A:1-((S)-2-Benzyloxycarbonylaminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid benzyl ester

To a stirred solution of the product from Step C, Example 1 (0.12 g,0.32 mmol) in DMF (10 mL) was added potassium carbonate (0.15 g, 1.05mmol) followed by benzyl 2-bromoacetate (0.08 g, 0.48 mmol) at roomtemperature and the mixture was heated at 70° C. for 20 h. A saturatedaqueous solution of ammonium chloride (20 mL) was added followed byethyl acetate (50 mL). The organic layer was separated and the aqueouswas extracted with ethyl acetate (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried and evaporated to a residue, whichwas purified by chromatography (silica, 50% ethyl acetate in hexane) togive a solid (0.11 g, 71%): mp 140-141° C.; MS (ES) m/z 484 (M⁺).

Step B:[(S)-2-(7-Hydroxymethyl-furo[2,3-g]indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

To a stirred solution of the product from Step A (0.13 g, 0.27 mmol) inethanol (10 mL) was added calcium chloride (0.06 g, 0.54 mmol) in THF (2mL) followed by sodium borohydride (0.04 g, 1.07 mmol) at 0° C. and themixture was stirred at room temperature for 20 h. The reaction mixturewas evaporated to a residue and a saturated aqueous solution of ammoniumchloride (20 mL was added followed by ethyl acetate (50 mL). The organiclayer was separated and the aqueous was extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine (30 mL),dried and evaporated to a residue, which was purified by chromatography(silica, 50% ethyl acetate in hexane) to give an oil (0.05 g, 49%); MS(ES) m/z 380 (M⁺).

Step C: [1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-yl]-methanol

A solution of the product from Step B (0.05 g, 0.13 mmol) in ethanol (5mL) was treated as described in Step E of Example 1, but using a mixtureof 9% methanol:1% ammonium hydroxide in dichloromethane aschromatography solvent to give the free base as an amorphous solid(0.032 g): mp 110-112° C.; MS (ES) m/z 246 (M⁺); ¹H NMR (DMSO-d₆) δ 8.16(s, 1H), 7.62 (d, 1H, J=9.2 Hz), 7.41 (d, 1H, J=9.2 Hz), 6.49 (s, 1.7H),4.65 (m, 3H), 4.55 (m, 1H), 3.53 (m, 1H), 1.03 (d, 3H, J=6.4 Hz).Analysis. Calculated for C₁₃H₁₈N₃O₂: C, 62.29; H, 6.27; N, 16.76. Found:C, 62.25; H, 6.09; N, 16.73.

EXAMPLE 3 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidamide Step A:1-((S)-2-Benzyloxycarbonylaminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid

To a solution of the product of Step A, Example 2 (0.15 g, 0.31 mmol) inethanol (10 mL) was added lithium hydroxide (0.026 g, 0.62 mmol) inwater (1 mL) and stirred at room temperature for 16 h. The reactionmixture was evaporated to a residue and a saturated aqueous solution ofammonium chloride (20 mL) was added followed by the addition ofphosphoric acid (1 M) until the solution was neutral. The mixture wasextracted with ethyl acetate (3×50 mL) and the combined extracts werewashed with brine (30 mL), dried and evaporated. The residue waspurified by chromatography (silica, dichloromethane, 5% methanol indichloromethane, 10% methanol in dichloromethane) to give an oil (0.12g, 98%): MS (ES) m/z 394 (M⁺); ¹H NMR (CD₃OD) δ 7.91 (s, 1H), 7.81 (s,1H), 7.58 (d, 1H, J=8.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 7.14-7.02 (m, 5H),4.81 (s, 2H), 4.49-4.42 (m, 2H), 4.17 (m, 1H), 1.18 (d, 3H, J=6.8 Hz).

Step B:[(S)-2-(7-Carbamoyl-furo[2,3-g]indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

To a stirred solution of the product from Step A (0.17 g, 0.43 mmol) inDMF (5 mL) was added 1-hydroxy-benzotriazole hydrate (0.029 g, 0.21mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.13 g, 0.65 mmol) followed by a solution of ammonia in dioxane (0.5 M,1.72 mL, 0.86 mmol). After 18 h, a saturated aqueous solution ofammonium chloride (20 mL) added and the mixture was extracted with ethylacetate (3×50 mL). The combined extracts were washed with brine, driedand evaporated. The residue was purified by chromatography (silica,dichloromethane, 5% methanol in dichloromethane) to give an oil (0.14 g,83%): MS (ES) m/z 393 (M⁺); ¹H NMR (CDCl₃) δ 8.20 (brs, 1H), 8.04 (s,1H), 8.01 (s, 1H), 7.69 (d, 1H, J=8.0 Hz), 7.32-7.23 (m, 6H), 6.76 (brs,2H), 5.03 (m, 2H), 4.63 (m, 2H), 4.40 (m, 1H), 1.16 (d, 3H, J=8.0 Hz).

Step C: 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidamide

A solution of the product from Step B (0.098 g, 0.25 mmol) in ethanol(10 mL) was treated as described in Step E of Example 1, but withoutchromatoghraphy, to give the fumarate salt (0.065 g): mp 170-172° C.; MS(ES) m/z 259 (M⁺); ¹H NMR (DMSO-d₆) δ 8.29 (s, 1H), 8.21 (s, 1H), 7.83(d, 1H, J=8.8 Hz), 7.67 (brs, 1H), 7.47 (d, 1H, J=8.8 Hz), 6.48 (s, 1H),4.71-4.54 (m, 2H), 3.54 (m, 1H), 1.06 (d, 3H, J=6.4 Hz). Analysis.Calculated for C₁₃H₁₄N₄O₂.1.0 C₄H₄O₄.0.2 H₂O. C, 54.02; H, 4.91; N,14.82. Found: C, 54.06; H, 5.25; N, 15.09.

EXAMPLE 4 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidmethyl amide fumarate

This compound was prepared by following a procedure similar to thatdescribed in Example 3, but replacing ammonia in dioxane withmethylamine hydrochloride in Step B to give the fumarate salt: mp180-182° C.; MS (ES) m/z 273 (M⁺); ¹H NMR (DMSO-d₆) δ 8.75 (q, 1H, J=4.4Hz), 8.21 (s, 1H), 8.19 (s, 1H), 7.82 (d, 1H J=8.8 Hz), 7.45 (d, 1H,J=8.8 Hz), 6.48 (s, 1H), 4.66-4.50 (m, 2H), 3.54 (m, 1H), 2.85 (d, 3H,J=4.4 Hz), 1.04 (d, 3H, J=6.4 Hz). Analysis. Calculated forC₁₄H₁₆N₄O₂.0.5 C₄H₄O₄.1.0 H₂O: C, 55.17; H, 5.79; N, 16.08. Found: C,54.86; H, 5.71; N, 15.69.

EXAMPLE 5 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(2-hydroxyethyl)-amide fumarate Step A:[(S)-2-[7-(2-Hydroxyethylcarbamoyl)-furo[2,3-g]indazol-1-yl]-1-methylethyl]-carbamicacid benzyl ester

A stirred solution of the product from Step A, Example 2 (0.44 g, 0.91mmol) in ethanolamine was heated at 80° C. for 8 h. A saturated aqueoussolution of ammonium chloride (20 mL) was added and the mixture wasextracted with ethyl acetate (3×50 mL). The combined extracts werewashed with brine, dried and evaporated to a residue, which was purifiedby chromatography (silica, 60% ethyl acetate in hexane) to give an oil(0.23 g, 57%): MS (ES) m/z 437 (M⁺); ¹H NMR (CDCl₃) δ 8.00 (s, 1H), 7.69(d, 1H, J=8.0 Hz), 7.22-7.30 (m, 7H), 5.30 (brs, 1H), 5.03 (m, 2H), 4.63(m, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.85 (m, 2H), 3.65 (m, 2H), 1.26(d, 3H, J=8.0 Hz).

Step B: 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(2-hydroxyethyl)-amide

A solution of the product from Step A (0.23 g, 0.52 mmol) in ethanol (10mL) was treated as described in Step C of Example 3 to give the fumaratesalt as an amorphous solid (0.14 g): MS (ES) m/z 303 (M⁺); ¹H NMR(DMSO-d₆) δ 8.78 (t, 1H, J=6.6 Hz), 8.29 (s, 1H), 8.23 (1H), 7.83 (d,1H, J=8.8 Hz), 7.47 (d, 1H J=8.8 Hz), 6.49 (s, 1H), 4.70-4.74 (m, 2H),3.54-3.61 (m, 3H), 3.37-3.41 (m, 2H), 1.06 (d, 3H, J=6.6 Hz). Analysis.Calculated for C₁₅H₁₈N₄O₃.1.0 C₄H₄O₄.1.75 H₂O: C, 50.72; H, 5.71; N,12.45. Found: C, 50.37; H, 5.68; N, 12.85.

EXAMPLE 6 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid[2-(3H-imidazol-4-yl)-ethyl]-amide fumarate

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A withhistamine to give the fumarate salt: mp 201-203° C.; MS (ES) m/z 353(M⁺); ¹H NMR (DMSO-d₆) δ 8.95 (t, 1H, J=6.6 Hz), 8.29 (s, 1H), 8.24 (s,1H), 7.84 (d, 1H, J=8.8 Hz), 7.56 (s, 1H), 7.48 (d, 1H, J=8.8 Hz), 6.86(s, 1H), 6.52 (s, 2H), 4.65-4.76 (m, 2H), 3.58 (m, 1H), 3.53-3.56 (m,2H), 2.81 (t, 2H, J=7.2 Hz), 1.08 (d, 3H, J=6.4 Hz). Analysis.Calculated for C₁₈H₂₀N₆O₂.1.3 C₄H₄O₄.1.3 H₂O: C, 52.90; H, 5.32; N,15.96. Found: C, 52.65; H, 5.33; N, 16.19.

EXAMPLE 7 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(2-morpholin-4-yl-ethyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with4-(2-aminoethyl)morpholine to give the fumarate salt as an amorphoussolid: MS (ES) m/z 373 (M⁺); ¹H NMR (DMSO-d₆) δ 8.81 (t, 1H J=6.6 Hz),8.34 (s, 1H), 8.24 (s, 1H), 7.99 (d, 1H J=8.8 Hz), 7.51 (d, 1H, J=8.8Hz), 6.55 (s, 4H), 4.65-4.84 (m, 2H), 3.58 (m, 1H), 3.53-3.56 (m, 5H),3.45 (m, 2H), 1.06 (d, 3H, J=6.4 Hz).

EXAMPLE 8 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(2-methoxyethyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with2-methoxyethylamine to give, after deprotection, the fumarate salt: mp75-76° C.; MS (ES) m/z 276 (M⁺); ¹H NMR (DMSO-d₆), δ 10.5 (1H, brs),8.92 (1H, t, J=5.2 Hz), 8.41 (1H, s), 8.31 (1H, s), 7.92 (1H, d, J=8.8Hz), 7.56 (1H, d, J+8.8 Hz), 6.61 (3H, s), 4.91-4.71 (2H, m), 3.75 (1H,m), 3.35 (3H, s), 1.16 (3H, d, J=11.2 Hz). Analysis. Calculated forC₁₆H₂₀N₄O₃.1.5 C₄H₄O₄.0.5 H₂O: C, 52.90; H, 5.45; N, 11.22. Found: C,52.71; H, 5.75; N, 11.05.

EXAMPLE 9 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(2-hydroxypropyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with1-aminopropan-2-ol to give, after deprotection, the fumarate salt: mp190-191° C.; MS (ES) m/z 317 (M⁺); ¹H NMR (DMSO-d₆) δ 8.65 (1H, t, J=2.6Hz), 8.28 (1H, s), 8.23 (1H, s), 7.85 (1H, d, J=9.2 Hz), 7.50 (1H, d,J=9.2 Hz), 6.61 (1H, s), 4.70-4.54 (2H, m), 3.83 (1H, m), 3.54 (1H, m),3.32-3.24 (2H, m), 1.11 (3H, d, J=6.4 Hz), 1.05 (3H, d, J=6.4 Hz).Analysis. Calculated for C₁₆H₂₀N₄O₃.0.7 C₄H₄O₄: C, 56.79; H, 5.78; N,14.09. Found: C, 56.42; H, 5.79; N, 14.39.

EXAMPLE 10 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid (1-hydroxy-cyclopropylmethyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with1-aminomethyl-cyclopropanol to give, after deprotection, the fumaratesalt: mp 77-79° C.; LC/MS m/z 329 [M+H]⁺; ¹H NMR (D₂O) δ 8.12 (d, J=1.8Hz, 1H), 7.74 (dd, J=8.4, 1.8 Hz, 1H), 7.68 (s, 1H), 7.35 (d, J=8.4 Hz,1H), 6.62 (s, 2H), 4.67 (m, 2H), 3.89 (m, J=6.0 Hz, 1H), 3.52 (s, 2H),1.23 (d, J=6.6 Hz, 3H), 0.74 (m, 2H), 0.67 (m, 2H). Analysis. Calculatedfor C₁₇H₂₀N₄O₃.C₄H₄O₄.1.5 H₂O.0.5 CH₄O: C, 52.38; H, 5.74; N, 10.86.Found: C, 52.27; H, 5.38; N, 10.89.

EXAMPLE 11 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid (3-hydroxy-2,2-dimethyl-propyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with3-amino-2,2-dimethylpropanol to give, after deprotection, the fumaratesalt: mp 103° C.; LC/MS m/z 345 [M+H]⁺; ¹H NMR (D₂O): δ 8.12 (s, 1H),7.75 (d, J=9.0 Hz, 1H), 7.65 (s, 1H), 7.34 (d, J=9.0 Hz, 1H), 6.65 (s,2.8H), 4.67 (m, 2H), 3.91 (s, 1H), 3.34 (s, 2H), 3.29 (s, 2H), 3.26 (s,2H), 1.24 (d, J=7.2 Hz, 3H), 0.90 (s, 6H). Analysis. Calculated forC₁₈H₂₄N₄O₃.1.5 C₄H₄O₄.0.5 H₂O.0.5 CH₄O: C, 54.14; H, 6.12; N, 10.31.Found: C, 54.10; H, 6.02; N, 10.47.

EXAMPLE 12 1-((S)-2-Amino-propyl)-1H-furo[2,3-g]indazole-7-carboxylicacid (3-acetylaminopropyl)-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A withN-(3-aminopropyl)-acetamide to give, after deprotection, the fumaratesalt: mp 81° C.; LC/MS m/z 358 [M+H]⁺; ¹H NMR (D₂O, 600 MHz): δ 8.22 (s,1H), 7.85 (d, J=9.0 Hz, 1H), 7.78 (s, 1H), 7.46 (dd, J=9.0, 0.6 Hz, 1H),6.69 (s, 2H), 4.78 (m, 2H), 4.00 (m, 1H), 3.47 (t, J=6.6 Hz, 2H), 3.29(t, J=6.6 Hz, 2H), 1.98 (s, 3H), 1.86 (hept, J=6.6 Hz, 2H), 1.32 (d,J=7.2 Hz, 3H). Analysis. Calculated for C₁₈H₂₃N₅O₃.1.25 C₄H₄O₄.H₂O: C,53.07; H, 5.81; N, 13.46. Found: C, 52.90; H, 5.65; N, 13.43.

Example 13 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid [3-(2-oxo-pyrrolidin-1-yl)-propyl]-amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with1-(3-aminopropyl)-pyrrolidin-2-one to give, after deprotection, thefumarate salt: mp 82° C.; LC/MS m/z 384 [M+H]⁺; ¹H NMR (D₂O): δ 8.26 (s,1H), 7.89 (d, J=9.0 Hz, 1H), 7.81 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 6.78(s, 3.4H), 4.82 (m, 2H), 4.05 (m, 1H), 3.57 (t, J=7.2 Hz, 2H), 3.47 (t,J=7.2 Hz, 2H), 3.43 (t, J=7.2 Hz, 2H), 2.45 (t, J=7.8 Hz, 2H), 2.07 (m,2H), 1.96 (m, 2H), 1.36 (d, J=6.6 Hz, 3H). Analysis. Calculated forC₂₀H₂₅N₅O₃.1.8 C₄H₄O₄.0.5 H₂O: C, 54.08; H, 5.53; N, 11.43. Found: C,54.03; H, 5.58; N, 11.43.

EXAMPLE 14 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylicacid (5-methyl-furan-2-ylmethyl)amide

This compound was prepared by following a procedure similar to thatdescribed in Example 5, but replacing ethanolamine in Step A with(5-methyl-furan-2-yl)-methylamine to give, after deprotection, thefumarate salt: mp 118-120° C.; LC/MS m/z 353 [M+H]⁺; ¹H NMR (D₂O): δ8.12 (s, 1H), 7.76 (d, J=9.0 Hz, 1H), 7.65 (d, J=0.6 Hz, 1H), 7.33 (dd,J=9.0, 0.6 Hz, 1H), 6.65 (s, 2.2H), 6.27 (d, J=3.0 Hz, 1H), 6.02 (d,J=1.8 Hz, 1H), 4.67 (t, J=6.6 Hz, 2H), 4.67 (t, J=6.6 Hz, 2H), 4.50 (s,2H), 3.92 (m, 1H), 2.24 (s, 3H), 1.27 (d, J=6.6 Hz, 3H). Analysis.Calculated for C₁₉H₂₀N₄O₃.1.25 C₄O₄.H₂O: C, 55.92; H, 5.28; N, 10.87.Found: C, 56.19; H, 5.26; N, 10.83.

EXAMPLE 15(S)-1-Methyl-2-[7-(3-methyl-1,2,4-oxadiazol-5-yl)-furo[2,3-g]indazol-1-yl]-ethylamineStep A: 1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acidmethyl ester

To a 50 mL round bottom flask containing NMP (20 mL), methylbromoacetate (0.35 g 2.3 mmol), and[2-(7-formyl-6-hydroxy-indazol-1-yl)-1-methyl-ethyl]-carbamic acidbenzyl ester (0.751 g, 2.1 mmol) was added K₂CO₃ (1.4 g, 10 mmol). Thismixture was heated to 90° C. for 16 h, then allowed to cool to 23° C.,decanted into a saturated aqueous NaHCO₃ solution (50 mL), and extractedwith ethyl acetate (2×20 mL). The combined extracts were dried (Na₂SO₄),filtered and concentrated. The crude product was purified bychromatography (silica gel, hexanes: ethyl acetate gradient, 3:1 to 1:1)to provide an oil: LC/MS m/z 408 [M+H]⁺; ¹H NMR (D₂O): δ 8.19 (s, 1H),8.06 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (bm,4H), 5.15 (d, 1H), 5.08 (dd, 2H), 4.8 (m, 1H), 4.6 (m, 1H), 4.29 (m,1H), 4.01 (s, 3H), 1.19 (d, J=6.6 Hz, 3H).

Step B:(S)-1-Methyl-2-[7-(3-methyl-1,2,4-oxadiazol-5-yl)-furo[2,3-g]indazol-1-yl]-ethylaminefumarate

To a 50 mL round bottom flask containing THF (5 mL), molecular sieves(0.80 g), sodium hydride (0.040 g, 1.0 mmol; 60% in mineral oil, washedwith hexanes) and acetamide oxime (0.07 g, 1.0 mmol). This mixture washeated to 50° C. for 1 h. The product from Step A (0.20 g, 0.50 mmol)was added and the mixture heated at reflux temperature for 2.5 h, thenallowed to cool to 23° C., decanted into a saturated aqueous NaHCO₃solution (50 mL), and extracted with dichloromethane (2×20 mL). Thecombined extracts were washed with a saturated aqueous NaHCO₃ solution(50 mL), dried (Na₂SO₄), filtered and concentrated. The crude productwas purified by chromatography (silica gel, methanol: dichloromethanegradient, 4% to 8%) to furnish the free base (0.049 g, 32%). Fumaricacid (0.019 g, 0.16 mmol) was added to a solution of the free base inmethanol (3 mL) concentration of the mixture provided the salt: mp187-9° C.; LC/MS m/z 298 [M+H]⁺; ¹H NMR (D₂O): δ 7.98 (d, J=3.0 Hz, 1H),7.78 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.52 (s,2.4H), 4.58 (m, 2H), 3.83 (m, 1H), 2.27 (s, 3H), 1.19 (d, J=6.6 Hz, 3H).Analysis. Calculated for C₁₅H₁₅N₅O₂.1.2 C₄H₄O₄.0.7 H₂O: C, 52.94; H,4.76; N, 15.59. Found: C, 53.07; H, 4.71; N, 15.61.

EXAMPLE 162-[1-((S)-2-Amino-propyl)-1H-furo[2,3-g]indazol-7-yl]-N-methyl-acetamideStep A:[(S)-2-(7-Cyanomethyl-furo[2,3-g]indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

A solution of the product from Example 2, Step B (0.55 g, 1.45 mmol) indichloromethane (20 mL) was cooled (ice bath), thionyl chloride (0.16mL, 2.18 mmol) was added, and the mixture was stirred for thirtyminutes. The reaction mixture was evaporated to a residue which wasdissolved in dichloromethane (20 mL) and evaporated. A solution ofsodium cyanide (0.29 g, 5.8 mmol) in DMSO (10 mL) was added to thisresidue and the mixture was stirred at room temperature for one hour.Saturated aqueous sodium bicarbonate (100 mL) was added and the mixturewas extracted with ethyl acetate (3×100 mL). The combined extracts werewashed with saturated aqueous sodium bicarbonate (2×150 mL), dried(MgSO₄) and evaporated to a tan solid (0.49 g, 87%): LC/MS m/z 389[M+H]⁺.

Step B: [1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-yl]-acetic acidmethyl ester

The product from Step A (0.48 g, 1.24 mmol) was added to doubledistilled 20% aqueous hydrochloric acid (5 mL) and heated at 90° C. forone hour and evaporated to a residue, which was treated with drymethanolic hydrochloric acid (0.5 N, 5 mL) at room temperatureovernight. The reaction was evaporated to give the methyl ester (0.25 g,61%): LC/MS m/z 288 [M+H]⁺.

Step C:2-[1-((S)-2-Amino-propyl)-1H-furo[2,3-g]indazol-7-yl]-N-methyl-acetamide

The product from Step B (0.25 g, 0.77 mmol) was combined with 2 Mmethanolic methylamine (10 mL, 20 mmol) and the mixture was stirred atroom temperature overnight. The reaction mixture was evaporated and theresidue purified by reversed phase chromatography (gradient,water/acetonitrile with 0.1% TFA). Evaporation of selected fractionsgave an oil (0.15 g; LC/MS 287 m/z) that was treated with methanolichydrochloric acid (0.5 N, 5 mL) and evaporated to give the methyl amideas an amorphous solid (0.15 g, 60%): LC/MS m/z 287 [M+H]⁺; ¹H NMR(CD₃OD) δ 8.167 (s, 1H), 7.65 and 7.39 (ABq, 2H, J=9Hz), 7.22 (s, 1H),4.80 (d, 2H, J=6 Hz), 3.97 (m, 1H, J=6 Hz, J=7 Hz), 3.85 (s, 2H), 2.81(s, 3H), 1.34 (d, 3H, 7 Hz). Analysis. Calculated for C₁₅H₁₈N₄O₂.2HCl.1.2 H₂O: C, 52.31; H, 6.26; N, 16.27. Found: C, 52.61; H, 6.12; N,15.93.

EXAMPLE 17N-[1-((S-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-nicotinamideStep A:[(S)-2-(7-Azidomethyl-furo[2,3-g]indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

A suspension of the product from Example 3, Step B (2.80 g, 7.39 mmol)in dichloromethane (30 mL) was cooled (ice bath), thionyl chloride (0.81mL, 11.1 mmol) was added and the mixture was stirred for 30 minutes.During the reaction the white suspension dissolved to a yellow solutionand then became a white suspension. The reaction was evaporated. Theresidue was treated with a solution of sodium azide (5 eq, 37 mmol, 2.4g) in DMSO (40 mL, heated at 70° C. to dissolve) with stirring and letcool to room temperature for 20 minutes. The reaction was quenched withsaturated aqueous sodium bicarbonate (100 mL) and extracted withdichloromethane (200 mL). The organic layer was washed with brine (100mL), dried (MgSO₄) and evaporated to give a yellow oil, 2.84 g. Thisresidue was purified by chromatography (silica gel, hexane/ethyl acetategradient) to give a colorless waxy residue, 2.45 g (82%) LC/MS m/z 405[M+H]⁺.

Step B:[(S)-2-(7-Aminomethyl-furo[2,3-g]indazol-1-yl)-1-methylethyl]-carbamicacid benzyl ester

A solution of the product from Step A (1.28 g, 3.17 mmol) in THF (25 mL)was stirred with polymer supported triphenylphosphine (4 eq, 3 mmol/g,12.7 mmol, 4.23 g) at 50° C. for 2 hours. Water (2.5 mL) was added andthe mixture was stirred for another hour; more water (5 mL) was addedand the reaction mixture was filtered. The solids were washed well withTHF and the filtrate was evaporated to a residue which was dried under avacuum to give a foam (1.10 g, 92%): LC/MS m/z 379 [M+H]⁺.

Step C:[(S)-1-Methyl-2-(7-{[(pyridine-3-carbonyl)-amino]-methyl}-furo[2,3-g]indazol-1-yl)-ethyl]-carbamicacid benzyl ester

To a solution of the product from Step B (0.32 g, 0.847 mmol) in THF (20mL) was added polymer supported di-isopropyl ethyl amine (3.86 mmol/g,0.44 g, 1.69 mmol, 2 eq); this suspension was cooled (ice bath) andnicotinoyl chloride (0.15 g, 0.847 mmol) was added. The ice bath wasremoved and mixture was stirred for one hour, additional nicotinoylchloride (50 mg) was added and the mixture was stirred at roomtemperature overnight. Triethylamine was added and after stirring for 10min saturated aqueous sodium bicarbonate (150 mL) was added. Thismixture was extracted with ethyl acetate (2×100 mL). The combinedextracts were dried (MgSO₄) and evaporated to an oil which was purifiedby chromatography (silica gel, hexane/ethyl acetate gradient) to give asolid (0.16 g, 39%): LC/MS m/z 484 [M+H]⁺.

Step D:N-[1-((S)-²-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-nicotinamide

To a solution of the product from Step C (0.16 g, 0.33 mmol) in methanol(20 mL) was added 10% Palladium on carbon (20 mg) and this mixture wasstirred under an atmosphere of hydrogen at room temperature for twodays. The reaction mixture was filtered and the filtrate evaporated togive a colorless oil (0.10 g, 87%): LC/MS m/z 350 [M+H]⁺; ¹H NMR (CD₃OD)δ 9.052 (s, 1H), 8.70 (m, 1H), 8.31 (m, 1H), 8.08 (s, 1H), 7.62 and 7.36(ABq, J=9 Hz, 2H), 7.56 (m, 1H), 4.50 (overlapping m and s, 4H), 3.47(m, 1H), 1.08 (d, 3H).

EXAMPLE 181-[1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-3-ethylureaStep A:((S)-2-{7-[(3-Ethylureido)-methyl]-furo[2,3-g]indazol-1-yl}-1-methylethyl)-carbamicacid benzyl ester

To a solution of the product from Example 17, Step B (0.20 g, 0.53 mmol)in THF (4 mL) was added polymer supported di-isopropylamine (1.5 eq,0.79 mmol, 0.22 g) and ethyl isocyanate (0.042 mL, 0.52 mmol); thismixture was stirred at room temperature for three hours followed by theaddition of methanol (5 mL). Dichloromethane (15 mL) was added and themixture was filtered, evaporation of the filtrate gave a solid (0.19 g)which was purified by chromatography (silica gel, hexane/ethyl acetategradient) to give a white solid (0.14 g, 59%): LC/MS m/z 450 [M+H]⁺.

Step B:1-[1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-3-ethylurea

Reaction of the product from Step A in a manner similar to thatdescribed in Example 17, Step D gave a colorless oil (98 mg: LC/MS m/z316 [M+H]⁺; ¹H NMR (CD₃OD) δ 7.97 (d, 1H), 7.49 and 7.23 (ABq, J=9 Hz,2H), 7.02 (s, 1H), 4.43 (s, 2H), 4.41 (m, 2H), 3.41 (m, J=6 Hz, 1H),3.08 (q, J=7 Hz, 2H), 1.01 (overlapping d and t, J=6 Hz and 7 Hz, 6H).

EXAMPLE 19N-(4-{[1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-sulfamoyl}-phenyl)-acetamideStep A:((S)-2-{7-[(4-Acetylamino-benzenesulfonylamino)-methyl]-furo[2,3-g]indazol-1-yl}-1-methyl-ethyl)-carbamicacid benzyl ester

A solution of the product from Example 17, Step B (0.32 g, 0.85 mmol) inTHF (10 mL) containing triethylamine (3.39 mmol, 0.47 mL) was cooled(ice bath) and N-acetylsulfanilyl chloride (0.20 g, 0.85 mmol) was addedfollowed by stirring for one hour. The reaction mixture was warmed toroom temperature, water (1 mL) was added, and stirring continued untilall the solids dissolved. Saturated aqueous sodium bicarbonate (150 mL)was added and the mixture was extracted with ethyl acetate (2×100 mL).The combined extracts were washed with brine (100 mL), dried (MgSO₄) andevaporated to a residue which was purified by chromatography (silicagel, hexane/ethyl acetate gradient) to give an amorphous solid (0.32 g,66%): LC/MS m/z 576 [M+H]⁺.

Step B:N-(4-{[1-((S)-2-Aminopropyl)-1H-furo[2,3-g]indazol-7-ylmethyl]-sulfamoyl}-phenyl)-acetamide

Reaction of the product from Step A in a manner similar to thatdescribed in Example 17, Step D gave a colorless solid (0.23 g, 94%): mp80-85° C.; LC/MS m/z 442 [M+H]⁺; ¹H NMR (CD₃OD) δ 7.93 (s, 1H), 7.53 and7.32 (ABq, 4H, 7 Hz), 7.45 and 7.08 (ABq, 2H, 9 Hz), 6.79 (s, 1H), 4.28(overlapping m and s, 4H), 3.29 (m, 1H, 6 Hz), 1.94 (s, 3H), 0.97 (d,3H, 6 Hz) Analysis. Calculated for C₂₁H₂₃N₅O₄S.0.4 H₂O: C, 56.21; H,5.35; N, 15.61. Found: C, 56.50; H, 5.31; N, 15.25.

EXAMPLE 20(S)-1-Methyl-2-[7-(4-pyridin-2-yl-piperazin-1-ylmethyl)-furo[2,3-g]indazol-1-yl]-ethylamineStep A:{(S)-1-Methyl-2-[7-(4-pyridin-2-yl-piperazin-1-ylmethyl)-furo[2,3-g]indazol-1-yl]-ethyl}-carbamicacid benzyl ester

A solution of the product from Example 3, Step B (0.18 g, 0.475 mmol) indichloromethane (20 mL) was cooled (ice bath) and thionyl chloride(0.052 mL, 0.71 mmol) added. The mixture was stirred for 30 min and thenevaporated to a residue which was dissolved in dichloromethane (20 mL);this solution was evaporated and the residue dried under a vacuum. Theresidue was dissolved in dichloromethane (20 mL) and1-(2-pyridyl)piperazine (0.5 mL, 3.4 mmol) was added, and the mixturewas stirred at room temperature for one hour at which point additional1-(2-pyridyl)piperazine (0.9 mL) was added. Solvent was removed byevaporation (45° C.) and THF (10 mL) was added, followed by heating themixture at reflux temperature for one hour. This reaction mixture wasevaporated and the residue dissolved in methanol (25 mL) andtriethylamine (1.5 mL) followed by evaporation of this mixture to aresidue which was purified by chromatography (silica gel, hexane/ethylacetate) to give a foamy solid (0.21 g, 84%): LC/MS m/z 525 [M+H]⁺.

Step B:(S)-1-Methyl-2-[7-(4-pyridin-2-yl-piperazin-1-ylmethyl)-furo[2,3-g]indazol-1-yl]-ethylamine

Reaction of the product from Step A in a manner similar to thatdescribed in Example 17, Step D gave a colorless oil (0.15 g, 96%):LC/MS m/z 391 [M+H]⁺; ¹H NMR (CD₃O) δ 7.97 (s, 2H), 7.52 (d, J=8 Hz,1H), 7.43 (m, 1H), 7.62 and 6.69 (ABq, J=9 Hz, 2H), 7.18 (s, 1H), 6.56(m, 1H), 4.39 (m, 2H), 3.75 (s, 2H), 3.44 (m, 4H), 3.36 (m, 1H), 2.61(br, 4H), 0.98 (d, J=7 Hz, 3H). Analysis. Calculated for C₂₂H₂₆N₆O.0.6H₂O: C, 65.85; H, 6.83; N, 20.94. Found: C, 65.95; H, 6.85; N, 20.58.

The compounds of the present invention can be used to lower and controlIOP including IOP associated with normotension glaucoma, ocularhypertension, and glaucoma in warm blooded animals including humans andother mammals. Since the treatment of glaucoma is preferably withcompounds that do not enter the CNS, relatively polar compounds that are5-HT₂ agonists are of particular interest. The compounds are preferablyformulated in pharmaceutical compositions which are preferably suitablefor topical delivery to the eye of the patient.

The compounds of this invention, Formula A, can be incorporated intovarious types of pharmaceutical compositions, such as ophthalmicformulations for delivery to the eye (e.g., topically, intracamerally;or via an implant). The compounds are preferably incorporated intotopical ophthalmic formulations for delivery to the eye. The compoundsmay be combined with ophthalmologically acceptable preservatives,viscosity enhancers, penetration enhancers, buffers, sodium chloride,and water to form an aqueous, sterile ophthalmic suspension or solution.Ophthalmic solution formulations may be prepared by dissolving acompound in a physiologically acceptable isotonic aqueous buffer.Further, the ophthalmic solution may include an ophthalmologicallyacceptable surfactant to assist in dissolving the compound. Furthermore,the ophthalmic solution may contain an agent to increase viscosity, suchas hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, orthe like, to improve the retention of the formulation in theconjunctival sac. Gelling agents can also be used, including, but notlimited to, gellan and xanthan gum. In order to prepare sterileophthalmic ointment formulations, the active ingredient is combined witha preservative in an appropriate vehicle, such as, mineral oil, liquidlanolin, or white petrolatum. Sterile ophthalmic gel formulations may beprepared by suspending the active ingredient in a hydrophilic baseprepared from the combination of, for example, carbopol-974, or thelike, according to the published formulations for analogous ophthalmicpreparations; preservatives and tonicity agents can be incorporated.

The compounds are preferably formulated as topical ophthalmicsuspensions or solutions, with a pH of about 5 to 8. The compounds willnormally be contained in these formulations in an amount 0.01% to 5% byweight, but preferably in an amount of 0.25% to 2% by weight. Thus, fortopical presentation 1 to 2 drops of these formulations would bedelivered to the surface of the eye 1 to 4 times per day according tothe discretion of a skilled clinician.

The compounds can also be used in combination with other agents fortreating glaucoma, such as, but not limited to, β-blockers (e.g.,timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol),carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), α₁antagonists (e.g., nipradolol), α₂ agonists (e.g. iopidine andbrimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandinanalogs (e.g., latanoprost, travoprost, unoprostone, and compounds setforth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444,“hypotensive lipids” (e.g., bimatoprost and compounds set forth in U.S.Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S.Pat. No. 4,690,931, particularly eliprodil and R-eliprodil, as set forthin a pending application U.S. Ser. No. 60/203,350, and appropriatecompounds from WO 94/13275, including memantine.

In the formulas described above, the alkyl group can be straight-chain,branched or cyclic and the like. Halogen includes Cl, Br, F, or I.Alkoxy is understood as an alkyl group bonded through an oxygen atom.

The compounds of the present invention preferably function as 5-HT₂agonists and preferably do not enter the CNS. Compounds having theability to be a 5-HT₂ agonist are beneficial for controlling IOP as wellas the treatment of glaucoma as shown in International Published PatentApplication No. WO 00/16761, incorporated in its entirety by referenceherein.

The compounds of the present invention preferably provide increasedchemical stability and preferably achieve the desired level oftherapeutic activity which includes a lowering or controlling of IOP.

The compounds of the present invention can be used in controlling orlowering IOP in warm blooded animals including humans. Preferably, aneffective amount of the compound is administered to the patient suchthat the IOP is controlled or lowered to acceptable levels. Furthermore,the compounds of the present invention can be used to treat glaucoma inwarm blooded animals, including humans, by administering an effectiveamount of the compound to a patient in need of such treatment to treatthe glaucoma. Pharmaceutically acceptable amounts of the compounds ofthe present invention will be readily understood by those skilled in theart to mean amounts sufficient to effect the desired therapy withouttoxicity or other deleterious effects on the patients' health. Examplesof such amounts include without limitation those amounts shown in theExamples.

Another embodiment of the present invention is a method of activating orbinding serotonin receptors, comprising administering an effectiveamount of at least one compound of the present invention to a patientusing an amount effective to activate or bind serotonin receptors,wherein such amount includes, but is not limited to, the dosage levelsdescribed herein.

The procedures described herein in Method 1 can be used to confirm acompound's 5-HT₂ binding affinity.

Method 1

5-HT₂ Receptor Binding Assay

To determine the affinities of serotonergic compounds at the 5-HT₂receptors, their ability to compete for the binding of the agonistradioligand [¹²⁵I]DOI to brain 5-HT₂ receptors is determined asdescribed below with minor modification of the literature procedure[Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat orhuman cerebral cortex homogenates (400 μL) dispersed in 50 mM TrisHClbuffer (pH 7.4) are incubated with [¹²⁵I]DOI (80 pM final) in theabsence or presence of methiothepin (10 μM final) to define total andnon-specific binding, respectively, in a total volume of 0.5 mL. Theassay mixture is incubated for 1 hour at 23° C. in polypropylene tubesand the assays terminated by rapid vacuum filtration over Whatman GF/Bglass fiber filters previously soaked in 0.3% polyethyleneimine usingice-cold buffer. Test compounds (at different concentrations) aresubstituted for methiothepin. Filter-bound radioactivity is determinedby scintillation spectrometry on a beta counter. The data are analyzedusing a non-linear, iterative curve-fitting computer program [TrendsPharmacol. Sci., 16, 413 (1995)] to determine the compound affinityparameter. The concentration of the compound needed to inhibit the[¹²⁵I]DOI binding by 50% of the maximum is termed the IC₅₀ or K_(i)value.

Method 2

5HT² Functional Assay: [Ca²⁺]_(i) Mobilization

The receptor-mediated mobilization on intracellular calcium ([Ca²⁺]_(i))was studied using the Fluorescence Imaging Plate Reader (FLIPR)instrument. Rat vascular smooth muscle cells, A7r5, were grown in anormal media of DMEM/10% FBS and 10 μg/mL gentamycin. Confluent cellmonolayers were trypsinized, pelleted, and re-suspended in normal media.Cells were seeded in a 50 μL volume at a density of 20,000 cells/well ina black wall, 96-well tissue culture plate and grown for 2 days.

On the day of the experiment, one vial of FLIPR Calcium Assay Kit dyewas re-suspended in 50 mL of a FLIPR buffer consisting of Hank'sBalanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH7.4. Cells were loaded with the calcium-sensitive dye by addition of anequal volume (50 μL) to each well of the 96-well plate and incubatedwith dye for 1 h at 23° C.

Typically, test compounds were stored at 25 μM in 50% DMSO/50% Ethanolsolvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol. For “hit”screening, compounds were further diluted 1:10 in FLIPR buffer andtested at a final concentration of 10 μM. For dose-response experiments,compounds were diluted 1:50 in FLIPR buffer and serially diluted 1:10 togive a 5- or 8-point dose-response curve.

The compound plate and cell plate were placed in the FLIPR instrument.At the beginning of an experimental run, a signal test was performed tocheck the basal fluorescence signal from the dye-loaded cells and theuniformity of the signal across the plate. The basal fluorescence wasadjusted between 8000-12000 counts by modifying the exposure time, thecamera F-stop, or the laser power. Instrument settings for a typicalassay were the following: laser power 0.3-0.6 W, camera F-stop F/2, andexposure time 0.4 sec. An aliquot (25 μL) of the test compound was addedto the existing 100 μL dye-loaded cells at a dispensing speed of 50μL/sec. Fluorescence data were collected in real-time at 1.0 secintervals for the first 60 secs and at 6.0 sec intervals for anadditional 120 secs. Responses were measured as peak fluorescenceintensity minus basal and where appropriate were expressed as apercentage of a maximum 5-HT-induced response [E_(max)%]. When thecompounds were tested as antagonists against 10 μM 5-HT, they wereincubated with the cells for 15 minutes prior to the addition of 5-HT.

Using the foregoing methods, 5-HT₂ binding affinities and agonistpotential can readily be determined.

The above procedures were used to generate the data shown in Table 1.

TABLE 1 5-HT_(2A) Receptor Binding and Functional Data 5HT_(2A(rat))5-HT_(2A(rat)) Example IC₅₀, nM EC₅₀, nM (E_(max)) E_(max) (%)  1 0.2163 101  2 0.53 18 86  3 2.3 158 87  4 0.81 54 98  5 3.5 55 94  6 0.66 5795  7 1.3 109 89  8 2.3 54 94  9 1.5 27 98 10 1.1 15 94 11 1.8 74 76 121.4 37 95 13 2.0 72 87 14 0.3 181 94 15 0.9 283 101 16 0.7 28 97 17 3.022 95 18 4.1 23 87 19 4.1 131 82 20 — 141 81 5-HT 0.9 56 101

TABLE 2 IOP Response in Conscious Cynomolgus Monkeys Percent IOPReduction ± Dose, SEM Hours after Dose Example μg Baseline IOP (mmHg) 13 6  3 300 32.8  9 ± 4 23 ± 4 27 ± 5  4 300 34.9 13 ± 3 30 ± 4 31 ± 4 11300 37.8 10 ± 5 23 ± 5 26 ± 5 (R)-DOI 100 31.9 11 ± 5 25 ± 3 34 ± 5IOP was determined with an Alcon Pneumatonometer after light cornealanesthesia with 0.1% proparacaine. Eyes were washed with saline aftereach measurement. After a baseline IOP measurement, test compound wasinstilled in one 30 μL aliquot to the right eyes only of nine cynomolgusmonkeys. Vehicle was instilled in the right eyes of six additionalanimals. Subsequent IOP measurements were taken at 1, 3, and 6 hours.

The following topical ophthalmic formulations are useful according tothe present invention administered 1-4 times per day according to thediscretion of a skilled clinician.

EXAMPLE 21

Ingredients Amount (wt %) Compound of Example 4 0.01-2% Hydroxypropylmethylcellulose  0.5% Dibasic sodium phosphate (anhydrous)  0.2% Sodiumchloride  0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 800.05% Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

EXAMPLE 22

Ingredients Amount (wt %) Compound of Example 4 0.01-2% Methyl cellulose 4.0% Dibasic sodium phosphate (anhydrous)  0.2% Sodium chloride  0.5%Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkoniumchloride 0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to7.3-7.4 Purified water q.s. to 100%

EXAMPLE 23

Ingredients Amount (wt %) Compound of Example 3 0.01-2%   Guar gum0.4-6.0% Dibasic sodium phosphate (anhydrous)  0.2% Sodium chloride 0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05%Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acid Foradjusting pH to 7.3-7.4 Purified water q.s. to 100%

EXAMPLE 24

Ingredients Amount (wt %) Compound of Example 11 0.01-2% Whitepetrolatum and mineral oil and lanolin Ointment consistency Dibasicsodium phosphate (anhydrous)  0.2% Sodium chloride  0.5% Disodium EDTA(Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkonium chloride0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. For example, it isunderstood that any of the compounds of the present invention may beformulated in the manner described in any of Examples 21-24. It isintended that the present specification and examples be considered asexemplary only with a true scope and spirit of the invention beingindicated by the following claims and equivalents thereof.

1. A method of treating glaucoma or lowering or controlling intraocularpressure in a subject comprising administering to the subject a compoundrepresented by the following Formula A:

wherein R, R¹ and R² are independently chosen from hydrogen, C₁₋₄alkyl;R³ is selected from hydrogen, C₁₋₄alkyl, or R² and R³ can complete apyrrolidine or piperidine ring, which can be substituted with C₁₋₄alkyl;R⁴ is hydrogen, halogen, C₁₋₄alkyl; R⁵ and R⁶ are independently chosenfrom hydrogen, halogen, C₁₋₆alkyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfoxide, nitrile, C₁₋₆alkyl substituted with halogen; R⁷ ischosen from C═OR⁹; S(O)_(m)R¹⁰; NR¹—(C═O)—R¹¹; C₁₋₆alkyl substitutedwith hydroxyl, C₁₋₆alkoxy, OC(═O)C₁₋₈, CO₂H, CO₂C₁₋₆alkyl, C(═O)NR¹²R¹³,S(O)_(m)NR¹²R¹³, NR¹⁴R¹⁵, phenyl or a saturated or unsaturated 5 or6-membered heterocyclic ring which can contain 1-4 heteroatoms selectedfrom N, O, or S and can be unsubstituted or substituted with C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl, phenyl or pyridinyl; or R⁷ can bechosen from a heterocyclic ring selected from oxazol-2-yl;4,5-dihydro-oxazol-2-yl; benzoxazol-2-yl; 5,6-dihydro-[1,3]oxazin-2-yl;thiazol-2-yl; 4,5-dihydro-thiazol-2-yl; benzothiazol-2-yl;imidazol-2-yl; imidazolidin-2-yl; [1,2,4]oxadiazol-5-yl;[1,2,4]oxadiazol-3-yl; [1,2,4]thiadiazol-5-yl; or[1,2,4]thiadiazol-3-yl, each of which can be unsubstituted orsubstituted with C₁₋₆alkyl, C₁₋₆alkoxy, phenyl, pyridinyl, or C₁₋₆alkylsubstituted with phenyl or pyridinyl; but R⁷ cannot be hydrogen, loweralkyl, hydroxyl, lower alkoxy, amino, mono- or di-loweralkyl amino,lower alkanoylamino, or halogen; R⁸ is selected from C₁₋₆alkyl, phenylwhich can be substituted with C₁₋₆alkyl, C₁₋₆alkoxy, NR¹(C═O)C₁₋₆alkyl,or halogen; R⁹ is chosen from hydroxyl; C₁₋₆alkoxy; C₁₋₆alkoxysubstituted with phenyl or pyridinyl which can be substituted withC₁₋₄alkoxy or halogen; NR¹⁶R¹⁷; C₁₋₆alkyl; or C₁₋₆alkyl substituted withhydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl, S(O)_(m)NR¹²R¹³,halogen, or phenyl or a heterocyclic ring selected from pyrrolidinyl,imidazoyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl, or tetrazolyl,or pyridinyl which can be unsubstituted or substituted with C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl; R¹⁰ is chosen from NR¹²R¹³;C₁₋₆alkyl; CH₂phenyl or CH₂pyridinyl which can be substituted withC₁₋₆alkyl, C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl; or C₂₋₆alkylsubstituted with hydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₆alkyl,phenyl, pyridinyl or imidazolyl which can be substituted with C₁₋₆alkyl,C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl; R¹¹ is NH₂; NR¹R²; C₁₋₆alkylsubstituted with hydroxyl, C₁₋₆alkoxy, CO₂H, CO₂C₁₋₆alkyl, phenyl or asaturated or unsaturated 5 or 6-membered heterocyclic ring which cancontain 1-4 heteroatoms selected from N, O, or S and can beunsubstituted or substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloC₁₋₄alkyl; R¹² and R¹³ are independently selected from hydrogen;C₁₋₆alkyl; CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl,thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can besubstituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl;C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, CO₂H, CO₂C₁₋₆alkyl,NR¹COC₁₋₆alkyl, or halogen; or R¹², R¹³, and the intervening nitrogenatom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy,C₁₋₄alkoxy or halogen; R¹⁴ and R¹⁵ are independently selected fromhydrogen, C₁₋₆alkyl, hydroxyl, C₁₋₆alkoxy, (C═O)—R¹¹, S(O)_(m)R⁸, phenylor pyridinyl which can be substituted with C₁₋₆alkyl, C₁₋₆alkoxy,halogen, or haloC₁₋₄alkyl; or R¹⁴, R¹⁵ and the nitrogen atom to whichthey are attached can form a heterocyclic ring selected frompyrrolidine, piperazine, or piperidine, which can be substituted withC₁₋₆alkyl, phenyl, or pyridinyl; R¹⁶ and R¹⁷ are independently selectedfrom hydrogen; C₁₋₆alkyl; hydroxyl; C₁₋₆alkoxy; CH₂Z, where Z isselected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl,pyrazinyl, or pyridazinyl, and which can be substituted with C₁₋₆alkyl,C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl; C₂₋₆alkyl substituted withhydroxyl, C₁₋₆alkoxy, halogen, NR¹(C═O)C₁₋₆alkyl, or a phenyl or aheterocyclic ring selected from pyrrolidin-2-yl; imidazo-2-yl;imidazo-4-yl; morpholin-3-yl; piperidin-4-yl; oxazolyl; isoxazolyl;thiazolyl; tetrazolyl; pyridinyl; each of which can be unsubstituted orsubstituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl,phenylC₁₋₄alkyl, oxo (═O); or R¹⁶, R¹⁷, and the intervening nitrogenatom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy, oxo(═O), C₁₋₄alkoxy, or phenyl; m is 0-2; A is N or CH; and X and Y areeither N or C, wherein X and Y cannot be the same; and the dashed bondsdenote a suitably appointed single and double bond.
 2. The method ofclaim 1, wherein for the compound of Formula A: R, R¹ and R² areindependently chosen from hydrogen, C₁₋₄alkyl; R³ is selected fromhydrogen, C₁₋₄alkyl, or R² and R³ can complete a pyrrolidine orpiperidine ring, which can be substituted with C₁₋₄alkyl; R⁴ ishydrogen, C₁₋₄alkyl; R⁵ and R⁶ are independently chosen from hydrogen,halogen, C₁₋₆alkyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl,C₁₋₆alkylsulfoxide, nitrile, C₁₋₆alkyl substituted with halogen; R⁷ ischosen from C═OR⁹; C₁₋₆alkyl substituted with hydroxyl; C₁₋₆alkoxy,OC(═O)C₁₋₈, CO₂H, CO₂C₁₋₆alkyl; C(═O)NR¹²R¹³, S(O)_(m)NR¹²R¹³, NR¹⁴R¹⁵,phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ringwhich can contain 1-4 heteroatoms selected from N, O, or S and can beunsubstituted or substituted with C₁₋₆alkyl; C₁₋₆alkoxy, halogen,haloC₁₋₄alkyl; phenyl or pyridinyl; or R⁷ can be chosen from aheterocyclic ring selected from oxazol-2-yl; 4,5-dihydro-oxazol-2-yl;benzoxazol-2-yl; 5,6-dihydro-[1,3]oxazin-2-yl; thiazol-2-yl;4,5-dihydro-thiazol-2-yl; benzothiazol-2-yl; imidazol-2-yl;imidazolidin-2-yl; [1,2,4]oxadiazol-5-yl; [1,2,4]oxadiazol-3-yl;[1,2,4]thiadiazol-5-yl; or [1,2,4]thiadiazol-3-yl, each of which can beunsubstituted or substituted with C₁₋₆alkyl, C₁₋₆alkoxy, phenyl,pyridinyl, or C₁₋₆alkyl substituted with phenyl or pyridinyl; but R⁷cannot be hydrogen, lower alkyl, hydroxyl, lower alkoxy, amino, mono- ordi-loweralkyl amino, lower alkanoylamino, or halogen; R⁸ is selectedfrom C₁₋₆alkyl, phenyl which can be substituted with C₁₋₆alkyl,C₁₋₆alkoxy, NR¹(C═O)C₁₋₆alkyl, or halogen; R⁹ is chosen from hydroxyl;C₁₋₆alkoxy; C₁₋₆alkoxy substituted with phenyl or pyridinyl which can besubstituted with C₁₋₄alkoxy or halogen; NR¹⁶R¹⁷; C₁₋₆alkyl; or C₁₋₆alkylsubstituted with hydroxyl, C₁₋₆alkoxy, NR¹²R¹³, CO₂H, CO₂C₁₋₄alkyl,S(O)_(m)NR¹²R¹³, halogen, or phenyl or a heterocyclic ring selected frompyrrolidinyl, imidazoyl, morpholinyl, oxazolyl, isoxazolyl, thiazolyl,or tetrazolyl, or pyridinyl which can be unsubstituted or substitutedwith C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl; R¹¹ is NH₂; NR¹R²;C₁₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, CO₂H, CO₂C₁₋₆alkyl,phenyl or a saturated or unsaturated 5 or 6-membered heterocyclic ringwhich can contain 1-4 heteroatoms selected from N, O, or S and can beunsubstituted or substituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen,haloC₁₋₄alkyl; R¹² and R¹³ are independently selected from hydrogen;C₁₋₆alkyl; CH₂Z, where Z is selected from phenyl, pyridinyl, furanyl,thiophenyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and which can besubstituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl;C₂₋₆alkyl substituted with hydroxyl, C₁₋₆alkoxy, CO₂H, CO₂C₁₋₆alkyl,NR¹COC₁₋₆alkyl, or halogen; or R¹², R¹³, and the intervening nitrogenatom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy,C₁₋₄alkoxy or halogen; R¹⁴ and R¹⁵ are independently selected fromhydrogen, C₁₋₆alkyl, hydroxyl, C₁₋₆alkoxy, (C═O)—R¹¹, S(O)_(m)R⁸, phenylor pyridinyl which can be substituted with C₁₋₆alkyl, C₁₋₆alkoxy,halogen, or haloC₁₋₄alkyl; or R¹⁴, R¹⁵ and the nitrogen atom to whichthey are attached can form a heterocyclic ring selected frompyrrolidine, piperazine, or piperidine, which can be substituted withC₁₋₆alkyl, phenyl, or pyridinyl; R¹⁶ and R¹⁷ are independently selectedfrom hydrogen; C₁₋₆alkyl; hydroxyl; C₁₋₆alkoxy; CH₂Z, where Z isselected from phenyl, pyridinyl, furanyl, thiophenyl, pyrimidinyl,pyrazinyl, or pyridazinyl, and which can be substituted with C₁₋₆alkyl,C₁₋₆alkoxy, halogen, or haloC₁₋₄alkyl; C₂₋₆alkyl substituted withhydroxyl, C₁₋₆alkoxy, halogen, NR¹(C═O)C₁₋₆alkyl, or a phenyl or aheterocyclic ring selected from pyrrolidin-2-yl; imidazo-2-yl;imidazo4-yl; morpholin-3-yl; piperidin-4-yl; oxazolyl; isoxazolyl;thiazolyl; tetrazolyl; pyridinyl; each of which can be unsubstituted orsubstituted with C₁₋₆alkyl, C₁₋₆alkoxy, halogen, haloC₁₋₄alkyl,phenylC₁₋₄alkyl, oxo (═O); or R¹⁶, R¹⁷, and the intervening nitrogenatom can form a heterocyclic ring selected from morpholine,thiomorpholine, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide,azetidine, pyrrolidine, piperidine, piperazine, unsubstituted orsubstituted with C₁₋₄alkyl or C₁₋₄alkyl substituted with hydroxy, oxo(═O), C₁₋₄alkoxy, or phenyl; m is 0-2; A is N; and X and Y are either Nor C, wherein X and Y cannot be the same; and the dashed bonds denote asuitably appointed single and double bond.
 3. The method of claim 2,wherein the compound of Formula A is:1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid amide;1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid methylamide fumarate;1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(1-hydroxy-cyclopropylmethyl)-amide; or1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(3-hydroxy-2,2-dimethyl-propyl)-amide.
 4. The method of claim 3, whereinthe compound of Formula A is1-((S)-2-aminopropyl)-1H-furo[2,3-g]indazole-7-carboxylic acid(3-hydroxy-2,2-dimethyl-propyl)-amide.